The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs
Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001565 |
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| author | Yuji Kashiwakura Nemekhbayar Baatartsogt Shoji Yamazaki Azusa Nagao Kagehiro Amano Nobuaki Suzuki Tadashi Matsushita Akihiro Sawada Satoshi Higasa Naoya Yamasaki Teruhisa Fujii Taemi Ogura Hideyuki Takedani Masashi Taki Takeshi Matsumoto Jun Yamanouchi Michio Sakai Masako Nishikawa Yutaka Yatomi Koji Yada Keiji Nogami Ryota Watano Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Akihiro Kume Hiroaki Mizukami Shizukiyo Ishikawa Yoichi Sakata Tsukasa Ohmori |
| author_facet | Yuji Kashiwakura Nemekhbayar Baatartsogt Shoji Yamazaki Azusa Nagao Kagehiro Amano Nobuaki Suzuki Tadashi Matsushita Akihiro Sawada Satoshi Higasa Naoya Yamasaki Teruhisa Fujii Taemi Ogura Hideyuki Takedani Masashi Taki Takeshi Matsumoto Jun Yamanouchi Michio Sakai Masako Nishikawa Yutaka Yatomi Koji Yada Keiji Nogami Ryota Watano Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Akihiro Kume Hiroaki Mizukami Shizukiyo Ishikawa Yoichi Sakata Tsukasa Ohmori |
| author_sort | Yuji Kashiwakura |
| collection | DOAJ |
| description | Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%–30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro, was mostly found in people in their 60s or of older age. The multivariate analysis suggested that “60s or older age” was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade. |
| first_indexed | 2024-04-13T21:42:52Z |
| format | Article |
| id | doaj.art-b43dde9c693b47fc933baa57f7dd8461 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-13T21:42:52Z |
| publishDate | 2022-12-01 |
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| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-b43dde9c693b47fc933baa57f7dd84612022-12-22T02:28:42ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127404414The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacsYuji Kashiwakura0Nemekhbayar Baatartsogt1Shoji Yamazaki2Azusa Nagao3Kagehiro Amano4Nobuaki Suzuki5Tadashi Matsushita6Akihiro Sawada7Satoshi Higasa8Naoya Yamasaki9Teruhisa Fujii10Taemi Ogura11Hideyuki Takedani12Masashi Taki13Takeshi Matsumoto14Jun Yamanouchi15Michio Sakai16Masako Nishikawa17Yutaka Yatomi18Koji Yada19Keiji Nogami20Ryota Watano21Takafumi Hiramoto22Morisada Hayakawa23Nobuhiko Kamoshita24Akihiro Kume25Hiroaki Mizukami26Shizukiyo Ishikawa27Yoichi Sakata28Tsukasa Ohmori29Department of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, JapanClinical Research Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi, JapanDepartment of Blood Coagulation, Ogikubo Hospital, 3-1-24 Imagawa, Suginami, Tokyo 167-0035, JapanDepartment of Laboratory Medicine, Tokyo Medical University Hospital, 6-7-1, Nishishinjuku, Shinjuku, Tokyo 160-0023, JapanDepartment of Transfusion Medicine, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya, Aichi 466-8560, JapanDepartment of Transfusion Medicine, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya, Aichi 466-8560, JapanDepartment of Respiratory Medicine and Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 633-8501, JapanDepartment of Respiratory Medicine and Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 633-8501, JapanHemophilia Treatment Center, Hiroshima University Hospital, 1-2-3 Kasumi, Minami, Hiroshima, Hiroshima 734-8551, JapanHemophilia Treatment Center, Hiroshima University Hospital, 1-2-3 Kasumi, Minami, Hiroshima, Hiroshima 734-8551, JapanHemophilia Treatment Center, Shizuoka Children’s Hospital, 860 Urushiyama, Aoi, Shizuoka, Shizuoka 420-8660, JapanDepartment of Joint Surgery, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, JapanDepartment of Pediatrics, St. Marianna University School of Medicine Hospital, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa 216-8511, JapanDepartment of Transfusion Medicine and Cell Therapy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, JapanDivision of Blood Transfusion and Cell Therapy, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime 791-0204, JapanDepartment of Pediatrics, Munakata Suikokai General Hospital, 5-7-1 Himakino, Fukutsu, Fukuoka 811-3298, JapanDepartment of Clinical Laboratory, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, JapanDepartment of Clinical Laboratory, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, JapanDepartment of Pediatrics, Nara Medical University Hospital, 840 Shijo, Kashihara, Nara 634-8522, JapanDepartment of Pediatrics, Nara Medical University Hospital, 840 Shijo, Kashihara, Nara 634-8522, JapanDivision of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanClinical Research Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDivision of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanCenter for Information, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Corresponding author Tsukasa Ohmori, Department of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%–30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro, was mostly found in people in their 60s or of older age. The multivariate analysis suggested that “60s or older age” was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade.http://www.sciencedirect.com/science/article/pii/S2329050122001565antibodiesneutralizingdependovirustreatment outcomegenetic therapyvirus vector |
| spellingShingle | Yuji Kashiwakura Nemekhbayar Baatartsogt Shoji Yamazaki Azusa Nagao Kagehiro Amano Nobuaki Suzuki Tadashi Matsushita Akihiro Sawada Satoshi Higasa Naoya Yamasaki Teruhisa Fujii Taemi Ogura Hideyuki Takedani Masashi Taki Takeshi Matsumoto Jun Yamanouchi Michio Sakai Masako Nishikawa Yutaka Yatomi Koji Yada Keiji Nogami Ryota Watano Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Akihiro Kume Hiroaki Mizukami Shizukiyo Ishikawa Yoichi Sakata Tsukasa Ohmori The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs Molecular Therapy: Methods & Clinical Development antibodies neutralizing dependovirus treatment outcome genetic therapy virus vector |
| title | The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs |
| title_full | The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs |
| title_fullStr | The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs |
| title_full_unstemmed | The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs |
| title_short | The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs |
| title_sort | seroprevalence of neutralizing antibodies against the adeno associated virus capsids in japanese hemophiliacs |
| topic | antibodies neutralizing dependovirus treatment outcome genetic therapy virus vector |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001565 |
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